A genome wide code to define cell-type specific CTCF binding and chromatin organization.

CTCF-mediated chromatin folding plays a key role in gene regulation, however the mechanisms underlying cell type-specific control are not fully elucidated. Comprehensive analyses reveal that CTCF binding stability and cohesin overlap in mice and humans is regulated by species specific differences in accessibility, the presence of CTCF extended Up and Downstream binding site sequences and motifs corresponding to expressed TFs enriched at most bound sites. CTCF repositions nucleosomes asymmetrically, with linker spacing altered by accessibility, while cohesin-mediated nucleosome phasing is affected by surrounding motifs that similarly impact chromatin insulation. Importantly, cell type-specific transcriptional programs determine motif enrichment at CTCF bound sites, reflecting the stabilizing/destabilizing effect of individual TFs. These studies identify mechanisms underlying cell type-specific CTCF profiles, linked to local and long-range chromatin organization.